Professor David I. Strutt

DavidProfessor of Developmental Genetics
Director of Research

Department of Biomedical Science
The University of Sheffield
Western Bank, Sheffield S10 2TN
United Kingdom

Room: D36 Firth Court
Telephone: +44 (0) 114 222 2372
email: d.strutt@sheffield.ac.uk


General

Career history

  • 2005: Professor of Developmental Genetics
  • 2003-present: Wellcome Senior Fellow in Basic Biomedical Science, University of Sheffield
  • 1998-2003: Lister Institute-Jenner Research Fellow, University of Sheffield
  • 1997-1998: Lecturer, University of Sheffield
  • 1993-1997: Postdoctoral Fellow, European Molecular Biology Laboratory, Heidelberg
  • 1991-1993: Postdoctoral Fellow, Department of Anatomy, University of Cambridge
  • 1988-1991: PhD, Department of Anatomy, University of Cambridge
  • 1985-1988: BA Natural Sciences, University of Cambridge

Research interests

Cell polarisation is a fundamental process in the development of complex multicellular organisms. We are interested in how such polarisation is coordinated and maintained during development, with a primary interest in the roles of the Frizzled sevenpass transmembrane receptor.

My research group is part of the  Bateson Centre, and the The Centre for Membrane Interactions and Dynamics (CMIAD)

Bateson Centre

CMIAD

Activities and distinctions

  • Wellcome Trust Senior Fellow in Basic Biomedical Science
  • Editorial board of Current Biology and Development
  • Lister-Jenner Fellow 1998-2003

Funding

Recent publications

Full publications list

Research

Understanding mechanisms of coordinated cell polarisation during animal development

Figure 1We study planar polarity in epithelia of the fruitfly Drosophila, and focus on two conserved mechanisms, the "core" planar polarity pathway and the Fat/Dachsous pathway. We aim to dissect the feedback and cell-cell communication mechanisms that mediate cellular symmetry breaking that is coordinated between cells. We exploit the strengths of genetic analysis in Drosophila and knowledge of biochemical interactions of the pathway components, and complement these with in vivo studies of protein behaviours and computational modelling.

Current research is focused on using fluorescently tagged pathway components, to carry out quantitative analyses of protein levels, distributions and dynamics (primarily using FRAP) and to combine these with computational modelling to test hypotheses (in collaboration with Prof Nick Monk). We are also beginning to exploit live, high-speed super-resolution microscopy (OMX SIM) to provide a more fine-grained view of protein behaviours. In parallel we are continuing efforts to identify new pathway components.

We have also initiated a collaboration (with Dr Nasreen Akhtar) to study the role of planar polarity in branching morphogenesis in a mammalian 3D primary culture model. Additionally, we are pursuing interests in mechanobiology, and in particular how planar polarity organises cell packing and vice versa.

Our long term goal is to understand how coordinated cell polarisation is achieved through the integrated spatiotemporal interactions of multiple pathway components acting over varying length-scales. In future we wish to begin to apply this knowledge to the mechanics of tissue morphogenesis, using both Drosophila and mammalian 3D culture models.

Lab Positions

Postgraduate studentship opportunities

1. Mechanisms of cell signalling and coordination of cell polarity in animal development

Tissue morphogenesis, repair and regeneration requires cells to communicate and coordinate their behaviours. Major pathways involved are the Wnt/Frizzled and Fat/Dachsous planar polarity pathways that mediate polarised cell signalling in epithelia sheets. Loss of their activity leads to a variety of developmental abnormalities in animal models such as failure of neural tube closure, cleft palates and heart defects, as well as deficits in wound healing and failure to repair kidney damage resulting in polycystic tubules, and is also implicated in cancer metastasis.

The project will focus on understanding molecular mechanisms of Wnt/Frizzled and Fat/Dachsous pathway activity, and in particular how individual proteins adopt polarised distributions with cells, and the signalling mechanisms that propagate this polarity from cell to cell. A molecular genetic approach will be used, taking advantage of the well-established model Drosophila, which provides sophisticated molecular and genetic and cell biological tools. A major focus in the lab is understanding protein dynamics during cell signalling, using techniques such as live imaging (both conventional and super-resolution) and FRAP, and combining this with genetic screens to identify new pathway components and cell biology and biochemical studies of protein behaviours. We combine these experimental studies with computation modelling approaches to aid in experimental design and hypothesis testing.

References

  • Hale, R., Brittle, A.L., Fisher, K.H., Monk, N.A. and Strutt, D. (2015) Cellular interpretation of the long-range gradient of Four-jointed activity in the Drosophila wing. eLife 4, e05789. [PMC4338440]
  • Strutt, H.*, Searle, E.*, Thomas-MacArthur, V., Brookfield, R. and Strutt, D. (2013) A Cul-3-BTB ubiquitylation pathway regulates junctional levels and asymmetry of core planar polarity proteins. Development 140: 1693-1702. [PMC3621487]
  • Brittle, A., Thomas, C. and Strutt, D. (2012) Planar polarity specification through the asymmetric subcellular localisation of the atypical cadherins Fat and Dachsous. Current Biology 22: 907-914. [PMC3362735]
  • Strutt, H.*, Warrington, S.J.* and Strutt, D. (2011) Dynamics of core planar polarity protein turnover and stable assembly into discrete membrane subdomains. Developmental Cell 20: 511-525. [PMC3094756]

2. Epithelial morphogenesis: coordinating planar polarity and tissue mechanics

Co-supervisor: Dr Alex Fletcher (Mathematics and Statistics)

As an organism develops, tissues are shaped and patterned in a coordinated way. The long-standing dogma of developmental biology is that secreted proteins diffuse to form expression gradients throughout tissues thereby providing spatial cues to direct growth, fate and pattern, drawing responses from cells even at some distance from the source. More recently, studies have revealed critical roles for mechanical forces in regulating morphogenesis, however, the interplay between these two systems is poorly understood. With the advent of fast 4D live imaging, combined with genetically encoded fluorescent sensors and sophisticated computational modelling tools, is it now possible to make major advances in understanding epithelial tissue dynamics at a quantitative systems level.

The model organism Drosophila provides an ideal system for dissecting mechanisms of morphogenesis in cell sheets, as it is highly amenable to genetic manipulation and has easily accessible simple tissues suitable for live imaging. The project will integrate cutting-edge genetic tools, advanced 4D fast live imaging and computational modelling in an iterative manner to: (i) explore how mechanical forces influence patterning and polarity; (ii) understand how cell division modulates tissue mechanics and coordinated cell polarity; and (iii) develop mathematical approaches to incorporate pattern and proliferation within existing modelling frameworks for epithelial morphogenesis.

We are looking for an enthusiastic and ambitious student to carry out this interdisciplinary project using both experimental and computational approaches. This project will be suitable for a student with a strong quantitative background (e.g. mathematics, physics, engineering or computer science) who is keen to apply their skills to a biological problem with potentially significant translational importance, or a student with a biological background but a strong interest and some skills in computational approaches. Moreover, the student will be provided with an interdisciplinary training, gaining valuable laboratory experience, particularly in high-level imaging and image analysis, as well as in mathematics and computational modelling.

References

  • Warrington SJ, Strutt H and Strutt D. (2013) The Frizzled-dependent planar polarity pathway locally promotes E-cadherin turnover via recruitment of RhoGEF2. Development 140(5):1045-1054.
  • Strutt H*, Warrington, SJ* and Strutt D. (2011) Dynamics of core planar polarity protein turnover and stable assembly into discrete membrane subdomains. Developmental Cell 20: 511-525.
  • Kursawe J, Brodskiy PA, Zartman JJ, Baker RE, Fletcher AG. Capabilities and Limitations of Tissue Size Control Through Passive Mechanical Forces. PLoS Comput Biol. 2015 Dec 29;11(12):e1004679.
  • Tetley RJ, Blanchard GB, Fletcher AG, Adams RJ, Sanson B. Unipolar distributions of junctional Myosin II identify cell stripe boundaries that drive cell intercalation throughout Drosophila axis extension. eLife. 2016 May 16;5:e12094.

To find out more about these projects and how to apply see our PhD opportunities page:

PhD Opportunities